First conditional marketing authorization approval in the European Union for hemophilia “A” gene therapy
Authors: Thierry VandenDriessche, Steven W. Pipe, Glenn F. Pierce, Radoslaw Kaczmarek
Journal: Molecular Therapy (2022)

Hemophilia A and B are bleeding disorders caused by defects in the coagulation factor VIII (FVIII) and FIX genes, respectively. If left untreated, persons with hemophilia are at risk for life-threatening bleeding episodes and repeated bleeding into joints, leading to crippling arthropathy. Current standard of care aims to prevent bleeding and preserve joint health through regular prophylaxis with clotting factor concentrates or, in the case of hemophilia A, substitution therapy with an FVIII mimetic. Over two decades ago, long-term correction of hemophilia was demonstrated after gene therapy in pre-clinical hemophilic animal models (reviewed in Evens et al.1Evens H. Chuah M.K. VandenDriessche T. Haemophilia gene therapy: from trailblazer to gamechanger. Haemophilia.Haemophilia. 2018; 24: 50-59https://doi.org/10.1111/hae.13494Crossref PubMed Scopus (19) Google Scholar). This helped to build momentum and consolidate hemophilia as a trailblazer for the gene therapy field. Paradoxically, it has been challenging to translate those early pre-clinical successes into an approved gene therapy product that could be used to treat patients with hemophilia. However, the European Commission (EC) has now granted conditional marketing authorization to Roctavian (valoctocogene roxaparvovec), an adeno-associated virus (AAV)5-based gene therapy product for the treatment of severe hemophilia A that is based on the expression of a B domain-deleted FVIII cDNA (https://www.ema.europa.eu/en/news/first-gene-therapy-treat-severe-haemophilia). This approval applies to adult patients without a history of neutralizing antibodies (clinically referred to as "inhibitors") to FVIII and without detectable antibodies to the AAV5 vector capsid. This conditional approval creates a new opportunity to treat patients with hemophilia A. This is also the first time that a liver-directed gene therapy product has been approved, at least conditionally, which has broad implications for the field at large. The European Medicines Agency (EMA)'s recommendation for conditional marketing approval is based primarily on the results of a non-randomized phase 3 clinical trial in 134 male patients with hemophilia A without a history of FVIII inhibitor and without detectable pre-existing antibodies to AAV5.2Ozelo M.C. Mahlangu J. Pasi K.J. Giermasz A. Leavitt A.D. Laffan M. Symington E. Quon D.V. Wang J.D. Peerlinck K. et al.Valoctocogene roxaparvovec gene therapy for hemophilia A.N. Engl. J. Med. 2022; 386: 1013-1025https://doi.org/10.1056/NEJMoa2113708Crossref PubMed Scopus (65) Google Scholar Two years after dosing in this phase 3 clinical trial—and up to five years after dosing in a supporting trial—most participants remained off prophylaxis and bleed free.2Ozelo M.C. Mahlangu J. Pasi K.J. Giermasz A. Leavitt A.D. Laffan M. Symington E. Quon D.V. Wang J.D. Peerlinck K. et al.Valoctocogene roxaparvovec gene therapy for hemophilia A.N. Engl. J. Med. 2022; 386: 1013-1025https://doi.org/10.1056/NEJMoa2113708Crossref PubMed Scopus (65) Google Scholar,3Pasi K.J. Laffan M. Rangarajan S. Robinson T.M. Mitchell N. Lester W. Symington E. Madan B. Yang X. Kim B. et al.Persistence of haemostatic response following gene therapy with valoctocogene roxaparvovec in severe haemophilia A.Haemophilia. 2021; 27: 947-956https://doi.org/10.1111/hae.14391Crossref PubMed Scopus (38) Google Scholar However, 85% individuals had asymptomatic elevations of alanine aminotransferase (ALT), signifying liver toxicity, most of whom received corticosteroids or other forms of immunosuppression. This is a common side effect in all systemically delivered AAV-based gene therapy trials. There has been inconsistent evidence of a cytotoxic T cell response, and immunosuppression has been variably effective at managing ALT elevations, suggesting that both immune and non-immune mechanisms are at play. Other unsolved issues include wide variability and uncertain durability of FVIII expression, which declines over a 2-year interval after vector injection. Decline in FVIII expression has also been reported in other AAV-based gene therapy trials for hemophilia A, suggesting that it is not a unique feature of treatment with valoctocogene roxaparvovec.4George L.A. Monahan P.E. Eyster M.E. Sullivan S.K. Ragni M.V. Croteau S.E. Rasko J.E.J. Recht M. Samelson-Jones B.J. MacDougall A. et al.Multiyear factor VIII expression after AAV gene transfer for hemophilia A.N. Engl. J. Med. 2021; 385: 1961-1973https://doi.org/10.1056/NEJMoa2104205Crossref PubMed Scopus (61) Google Scholar It is intriguing that, in contrast to FVIII, FIX levels have appeared more stable after AAV hemophilia B gene therapy. Although several potential immune and non-immune mechanisms have been proposed,5Butterfield J.S. Yamada K. Bertolini T.B. Syed F. Kumar S.R. Li X. Arisa S. Piñeros A.R. Tapia A. Rogers C.A. et al.IL-15 blockade and rapamycin rescue multifactorial loss of factor VIII from AAV-transduced hepatocytes in hemophilia A mice.Mol. Ther. 2022; (S1525-0016(22)00426-9)https://doi.org/10.1016/j.ymthe.2022.07.005Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar the mechanism of FVIII decline in the clinic is also not understood. It has been shown in pre-clinical studies that hepatic FVIII expression after gene therapy could trigger a cellular endoplasmic reticulum (ER) stress response that contributes to decline in FVIII expression. It is therefore tempting to speculate that the apparent different outcomes in the FVIII and FIX gene therapy clinical trials may be mainly due to differences in the therapeutic transgenes. However, recent liver biopsy analyses in the valoctocogene roxaparvovec trial participants 2.6–4.1 years after vector dosing did not find evidence of ER stress but did show evidence of transcriptional silencing in one participant.6Fong S. Yates B. Sihn C.R. Mattis A.N. Mitchell N. Liu S. Russell C.B. Kim B. Lawal A. Rangarajan S. et al.Interindividual variability in transgene mRNA and protein production following adeno-associated virus gene therapy for hemophilia A.Nat. Med. 2022; 28: 789-797https://doi.org/10.1038/s41591-022-01751-0Crossref PubMed Scopus (19) Google Scholar Moreover, given the complex differences between different trials in terms of vector dose, serotype, manufacturing, design, and/or patient populations, it cannot be ruled out that these confounding variables may also have affected the apparent different kinetics in FVIII and FIX transgene expression. This being a conditional marketing authorization approval, the EMA recognized the remaining uncertainties and imposed specific obligations that would need to be fulfilled for full approval. These include submitting a 5-year follow up of the phase 3 trial results in 2025, as well as the final results of an ongoing phase 3 trial in patients receiving a prophylactic corticosteroid regimen in 2027, aiming to establish an adequate corticosteroid regimen and identify predictive factors for no or low response in adults with severe hemophilia. Ultimately, to ensure the long-term efficacy and safety of this gene therapy, EMA requires that the treated patients be monitored for 15 years. Valoctocogene roxaparvovec has not yet been filed with the US FDA. Although there is no direct equivalent to the EMA's conditional approvals at the FDA, the agency may require the submission of a Risk Evaluation and Mitigation Strategy (REMS) as a condition of approving a drug if they determine that such a strategy is necessary to ensure that the benefits of the drug outweigh the risks. Considering the uncertainties, the National Hemophilia Foundation submitted a citizen petition to the FDA urging the agency to require a REMS as a condition of approval for both valoctocogene roxaparvovec and etranacogene dezaparvovec (a gene therapy for hemophilia B, currently under FDA review). Conditional approval of the first gene therapy product for hemophilia is undoubtedly an important milestone for those patients and their families who are affected by this severe bleeding disorder. This would be especially true in lower-income countries, where treatment does not exist or is suboptimal. This gene therapy treatment will complement existing treatments for hemophilia A and is the only approach that provides multi-year therapeutic effects following a single treatment. However, in the face of the outstanding questions that remain to be addressed in terms of long-term efficacy and safety in line with the EMA recommendations, evidence to date shows that it is not yet the bona fide cure that the hemophilia community has been awaiting. Specifically, efforts should continue to decipher and minimize the risk of liver toxicity, reduce inter-patient variability, and stabilize FVIII expression levels within a normal physiologic range. Importantly, the ability to re-treat patients with suboptimal or declining FVIII levels cannot yet be achieved, given the marked immune response that follows AAV therapy.7Kaczmarek R. Pierce G.F. Noone D. O'Mahony B. Page D. Skinner M.W. Eliminating Panglossian thinking in development of AAV therapeutics.Mol. Ther. 2021; 29: 3325-3327Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar Following this conditional regulatory approval, the present and future of hemophilia gene therapy can perhaps be best synthesized by paraphrasing Winston Churchill: "Now this is not the end, it is not even the beginning of the end. But it is, perhaps, the end of the beginning." T.V. received funding from Takeda, Pfizer, and Catalyst Biosciences, speaker honoraria from Takeda, Pfizer, BioMarin, and Biotest, and research grants for gene therapy (European Union Horizon 2020 UPGRADE project under grant agreement N°825825 and Vrije Universiteit Brussel – IOF GEAR). R.K. has received funding from the Bayer Hemophilia Awards Program. S.W.P. is a consultant to Apcintex, ASC Therapeutics, Bayer, Biomarin, CSL Behring, GenVentiv, HEMA Biologics, Freeline, LFB, Novo Nordisk, Pfizer, Regeneron/Intellia, Roche/Genentech, Sanofi, Takeda, Spark Therapeutics, and uniQure. G.F.P. is a consultant for Decibel Therapeutics, Frontera, Intellia, Pfizer, Regeneron, Spark Therapeutics, and Third Rock Ventures, is on the boards of World Federation of Hemophilia and Voyager Therapeutics, and has received speaker fees from BioMarin.